EP2986617A1 - Antibakterielle siderophor-aminopenicillin-konjugate - Google Patents

Antibakterielle siderophor-aminopenicillin-konjugate

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Publication number
EP2986617A1
EP2986617A1 EP13882608.6A EP13882608A EP2986617A1 EP 2986617 A1 EP2986617 A1 EP 2986617A1 EP 13882608 A EP13882608 A EP 13882608A EP 2986617 A1 EP2986617 A1 EP 2986617A1
Authority
EP
European Patent Office
Prior art keywords
compound
bacterial infection
conjugates
bacterium
gram
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13882608.6A
Other languages
English (en)
French (fr)
Other versions
EP2986617A4 (de
Inventor
Marvin J. Miller
Cheng Ji
Patricia A. MILLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Notre Dame
Original Assignee
University of Notre Dame
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Notre Dame filed Critical University of Notre Dame
Publication of EP2986617A1 publication Critical patent/EP2986617A1/de
Publication of EP2986617A4 publication Critical patent/EP2986617A4/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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Definitions

  • Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium that endangers immunocompromised patients, including those with cystic fibrosis (CF), cancer, or AIDS. Once the infection is established it is very difficult to eradicate because P. aeruginosa is intrinsically resistant to many of existing antibiotics, including ⁇ -lactams. Inadequate penetration through the cell envelope is a significant factor in the resistance of P. aeruginosa to ⁇ -lactam antibiotics such as ampicillin and amoxicillin.
  • strains of P. aeruginosa have developed receptors to recognize and transport Fe(III)-siderophore complexes from other species
  • Enterobactin is a tris- catecholate siderophore primarily found in Gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium. Enterobactin can also promote iron uptake into P. aeruginosa and the uptake is specifically inducible by enterobactin under iron-limiting conditions. Using enterobactin as a shuttle to deliver antibiotics into P. aeruginosa and other producing bacteria is an attractive strategy to pursue. However, this approach would be synthetically challenging because enterobactin has no functionality or site suitable for drug conjugation. Thus, new siderophore conjugates are needed to advance the study of antibiotic selectivity and to provide antibiotics effective against drug-resistant bacteria.
  • the invention provides synthetic conjugates of a relatively simple siderophore mimic and various antibiotics.
  • the conjugates can demonstrate selectively potent anti-bacterial activity, including anti-pseudomonal activity, while the parent antibiotics, themselves, are inactive.
  • the invention this provides iron transport-mediated drug delivery systems comprising the compounds described herein.
  • the compound can include a tris-catecholate siderophore with a tripodal backbone and as a conjugate with an antibiotic such as ampicillin or amoxicillin.
  • the conjugates can be assimilated by an induced bacterial iron transport process and their activities are typically inversely related to iron concentration.
  • the easily synthesized tris-catecholate siderophores can be used to prepare various drug conjugates to target antibiotic -resistant Gram-negative bacteria.
  • X is an antibiotic covalently linked to the illustrated structure of Formula (I) via an ester or amide bond;
  • n 0 or 1-11;
  • each R is independently H, alkyl, alkoxy, hydroxy, carboxy, halo, nitro, amino, or cyano;
  • each n is independently 1, 2, or 3;
  • each R 1 is a (Ci-C6)alkanoyl group. In one embodiment, each R 1 is acetyl, propanoyl, or benzoyl. In one specific embodiment, each R 1 is acetyl. In another specific embodiment, each R 1 is H.
  • each R is H, alkyl, alkoxy, or hydroxy.
  • each R 2 is H.
  • R 2 can also be a substituent as described below for the definition of substituents.
  • each R 1 is the same, while in other embodiments, R 1 groups can be different. Likewise, in various embodiments, each R can be the same, while in other embodiments, R groups can be different from each other, for example, depending on the starting material selected to prepare the compounds.
  • each n is 1. In other embodiments, n can be independently 1, 2 or 3; or 1 or 2; or 2 or 3. In some embodiments, m can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or a range from any one of the aforementioned integers to any other of the aforementioned integers. In various embodiments, m is 0, 1, 2, or 3. In some embodiments, the carbon of the parentheses marked by the letter m and its adjacent methylene can be replaced by a linker as defined below.
  • variable X can be, for example, amikacin, amoxicillin, ampicillin, amphotericin, bacillomycin, cefalotin, chloramphenicol, chlortetracycline, ciprofloxacin, clindamycin, clindamycin phosphate, cycloserince, daptomycin, demeclocycline, doxorubicin, doxycycline, erythromycin, ethambutol, erythromycin, gentamicin, isoniazid, kanamycin, lincomycin, loracarbef, methacycline, mupirocin, neomycin, nystatin, oxytetracycline, pyrrolnitrin, rifampin, rolitetracycline, streptomycin, sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine,
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • the invention further provides methods of treating a Gram-negative bacterial infection.
  • the methods can include administering to a subject in need thereof an effective therapeutic amount of a compound described herein, thereby treating the bacterial infection.
  • the invention yet further provides methods of killing or inhibiting the growth of a Gram- negative bacterium where the methods include contacting the bacterium with an effective lethal or inhibitory amount of a compound described herein.
  • the bacterial infection can be caused by an antibiotic-resistant bacterium.
  • the bacterial infection is caused by a Pseudomonal bacterium.
  • the bacterial infection can be caused by Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, or Salmonella typhimurium.
  • the invention also provides a method of increasing the permeability of a Gram- negative bacterium cell membrane to an antibiotic comprising conjugating an antibiotic to a compound of Formula (A) to provide a compound of Formula (I), and administering the compound to the bacterium cell membrane, thereby increasing the permeability of the Gram- negative bacterium cell membrane to the antibiotic as a result of its conjugation to the siderophore.
  • the invention additionally provides novel compounds of the formula described herein, intermediates for the synthesis of the compounds, as well as methods of preparing the compounds.
  • the invention also provides compounds of the formulas described herein that are useful as intermediates for the synthesis of other useful compounds.
  • the invention provides iron transport-mediated drug delivery compounds and methods. The synthesis and efficacy of the compounds have been evaluated and selective anti-pseudomonal compounds have been discovered.
  • the invention provides various synthetic conjugates of a relatively simple siderophore mimic and antibiotics, which conjugates have selectively potent anti-bacterial activity, while the parent antibiotics, themselves, are less active or substantially completely inactive. Investigation of receptor binding and transport of Fe(III)-enterobactin has revealed that an unsubstituted triscatechol iron center and the coordinated catechol amide groups are essential for recognition as a siderophore. To develop practical syntheses of microbe- selective sideromycins, simplified symmetrical siderophore analogs like 2 ( Figure 1) with linkers remote from the site of iron binding were developed as suitable scaffolds for conjugation to antibiotics.
  • Reagents and conditions (a) 1. BH 3 -THF, THF, reflux; 2. Boc 2 0, Et 3 N, MeOH, reflux, 83% for 2 steps; (b) NiCl 2 , NaBH 4 , MeOH, sonication, rt, 92%; (c) Methyl succinyl chloride, Et N, CH 2 C1 2 , 0 °C to rt, 75%; (d) 6 N HC1, reflux, 100%; (e) 2,3-Diacyloxybenzoyl chloride 8, aqueous NaHC0 3 /THF, 0 °C to rt, 57%; (f) 1.
  • acylated catecholates as the siderophore components has the benefit of not only facilitating synthesis but also preventing pharmacological side effects of the catechol groups.
  • the acylated catecholates can serve as prodrugs to the required iron binding catechols while circumventing potential methylation by a catechol O-methyltransferase (COMT) that would lead to a permanent loss of effective iron binding ability necessary for siderophore activity.
  • COMP catechol O-methyltransferase
  • triamino acid 7 was acylated with 2,3-diacyloxybenzoyl chloride 8 in aqueous sodium bicarbonate to give tripodal siderophore 9, which can serve as a common intermediate for attachment of various amino or hydroxyl-containing drugs via an amide or ester linkage.
  • Various analogs of compound 9 can be prepares, such as compounds of Formula (A), to serve as an analogous intermediate for conjugation to antibiotics.
  • conjugates 10 and 11 were first evaluated for their antibacterial ability against a collection of strains of P.
  • the parent drugs ampicillin and amoxicillin, were inactive or only weakly active against wild type strains of P. aeruginosa (KW799/wt, PAOl, Pa4, and Pa6) due to low membrane permeability. This was confirmed by studies of inhibition of the P. aeruginosa permeable mutant K799/61 in the assay, where both drugs are highly active as indicated by the large zones of inhibition they induced. Thus, strains of P. aeruginosa have the target of these classical antibiotics, but they cannot normally be accessed by passive diffusion. Table 1. Diameter of growth inhibition zones (mm) in the agar diffusion antibacterial susceptibility assay.
  • P. aeruginosa K648 (pvd-, pch- o 15 o 17 o o o o )
  • DMSO/MeOH was added to 9 mm wells in agar media (Standard I Nutrient Agar, Serva or Mueller Hinton II Agar, Becton, Dickinson and Company); Inhibition zones were read after incubation at 37 °C for 24 hours.
  • conjugates 10 and 11 represent the increased expression of appropriate siderophore receptors at the pathogen cell surface under iron limited conditions. This was demonstrated in assays with P. aeruginosa K648, a strain deficient for its native siderophore pyoverdin and pyochelin biosynthesis. While both conjugates 10 and 11 were inactive against the K648 strain in the iron-rich medium, the activities were largely elevated when tested in the iron-deficient medium, indicating that uptake of the conjugates was induced under iron-restricted conditions.
  • both conjugates 10 and 11 showed no activity against a clinical isolate P. aeruginosa Pa6 even under iron-deficient conditions, potentially because Pa6 as well as PAOl and Pa4 are different from each other in the type of pyoverdins they produce and utilize.
  • Conjugates 10 and 11 were subjected to further assays to determine their minimum inhibitory concentrations (MIC in ⁇ ) in both iron-rich and iron-deficient media (Table 2). Both conjugates exhibited excellent antibacterial activity against the various wild type strains of P. aeruginosa in iron-deficient medium, with MICs ranging from 0.05 to 0.39 ⁇ , while ampicillin and amoxicillin were generally inactive (>100 ⁇ ). The only exception was Pa6, against which both conjugates were inactive, consistent with the observation from the agar diffusion assay.
  • K.pneumoniae ATCC 8303 X68 >200 >ioo >200 >ioo >200 >ioo 100 >ioo a MIC 9 o values ( ⁇ ) were determined using the broth microdilution method in Mueller- Hinton broth No.2 (MHII) with visual end point analysis according to the CLSI guidelines (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 8th ed. (Villanova, PA, USA), Clinical and Laboratory Standards Institute (CLSI), 2009, approved standard document M07-A7).
  • MHII Mueller- Hinton broth No.2
  • Klebsiella pneumoniae both of which are able to synthesize and utilize enterobactin and its degraded product for iron uptake under iron-limited conditions.
  • conjugate 10 When tested against E. coli, conjugate 10 showed an 8-fold increase relative to ampicillin while conjugate 11 was almost as equipotent as amoxicillin.
  • both conjugates In sharp contrast to the activity enhancement observed in P. aeruginosa strains, both conjugates were found to be inactive (>100 ⁇ ) against K.
  • references in the specification to "one embodiment”, “an embodiment”, etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.
  • the term “about” can refer to a variation of + 5%, + 10%, + 20%, or + 25% of the value specified.
  • “about 50" percent can in some embodiments carry a variation from 45 to 55 percent.
  • the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percents, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.
  • ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values.
  • a recited range e.g., weight percentages or carbon groups
  • Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.
  • contacting refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.
  • An "effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
  • an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art.
  • an “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
  • an “effective amount” generally means an amount that provides the desired effect.
  • treating include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
  • the terms “treat”, “treatment”, and “treating” can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated.
  • treatment can include medical, therapeutic, and/or prophylactic administration, as appropriate.
  • inhibitor refers to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells.
  • the inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.
  • Generic terms include each of their species.
  • halo includes and can explicitly be fluoro, chloro, bromo, or iodo.
  • alkyl refers to a branched, unbranched, or cyclic hydrocarbon having, for example, from 1-20 carbon atoms, and often 1-12, 1- 10, 1-8, 1-6, or 1-4 carbon atoms.
  • Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (isopropyl), 1- butyl, 2-methyl- 1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (i-butyl), 1-pentyl,
  • the alkyl can be unsubstituted or optionally substituted, for example, with a substituent described below.
  • the alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can optionally include both alkenyl or alkynyl groups, in certain embodiments.
  • the alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene), depending on the context of its use.
  • alkoxy refers to the group alkyl-O-, where alkyl is as defined herein.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, w-propoxy, iso- propoxy, w-butoxy, iert-butoxy, sec-butoxy, w-pentoxy, w-hexoxy, 1,2-dimethylbutoxy, and the like.
  • the alkoxy can be unsubstituted or substituted.
  • aryl refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • the radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system.
  • the aryl group can have from 6 to 20 carbon atoms, for example, about 6- 10 carbon atoms, in the cyclic skeleton.
  • the aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl,
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • the aryl can be unsubstituted or optionally substituted, as described for alkyl groups.
  • a “linker” or “linking group” refers to an organic or inorganic chain or moiety that connects to other groups of a molecule.
  • substituted indicates that one or more (e.g., 1, 2, 3, 4, or 5; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogen atoms on the group indicated in the expression using "substituted” is replaced with a "substituent".
  • the substituent can be one of a selection of the indicated group(s), or it can be a suitable group known to those of skill in the art, provided that the substituted atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • Suitable substituent groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, aroyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclesulfinyl, heterocyclesulfonyl, phosphate, sulfate, hydroxyl amine
  • solvate refers to a solid compound that has one or more solvent molecules associated with its solid structure. Solvates can form when a solid compound is crystallized from a solvent, wherein one or more solvent molecules become an integral part of the solid crystalline matrix.
  • the compounds of the formulas described herein can be solvates, for example, ethanol solvates.
  • Another type of a solvate is a hydrate.
  • a "hydrate” likewise refers to a solid compound that has one or more water molecules intimately associated with its solid or crystalline structure at the molecular level. A hydrate is a specific type of a solvate.
  • Hydrates can form when a compound is solidified or crystallized in water, wherein one or more water molecules become an integral part of the solid crystalline matrix.
  • the compounds of the formulas described herein can be hydrates.
  • An antibiotic is an agent that inhibits bacterial or fungal growth or kills bacteria or fungi.
  • Antibiotics can be linked to the structure of Formula (I) via an amide or other linking group. Accordingly, any antibiotic that has an available hydroxyl or amino group can be linked to the structure of Formula (A), either by direct condensation of an amine and the a carboxy group of Formula (A), such as in compound 9, or by first carrying out a functional group transformation of a hydroxyl of the antibiotic to an amine, followed by amide formation with Formula (A).
  • Antibiotics that can be linked to Formula (A) to provide a compound of Formula (I) include, but are not limited to, antibiotics of the lincomycin family (a class of antibiotic agents originally recovered from streptomyces lincolnensis); antibiotics of the tetracycline family (a class of antibiotic agents originally recovered from streptomyces aureofaciens); and sulfur-based antibiotics such as the sulfonamides.
  • antibiotics of the lincomycin family a class of antibiotic agents originally recovered from streptomyces lincolnensis
  • antibiotics of the tetracycline family a class of antibiotic agents originally recovered from streptomyces aureofaciens
  • sulfur-based antibiotics such as the sulfonamides.
  • a wide variety of antibiotics can be conjugated to Formula (A), such as the antibacterials described at http://en.wikipedia.org/wiki/Antibacterial. Some specific useful examples include the following.
  • Beta-lactams that can be conjugated include penems, carbapenems (imipenem, meropenem, ertapeneme, doripenem, panipenem, biapenem, and the like), monobactams (aztreonam, tigimonam, carumonam, BAL30072, and the like), as well as a variety of other beta-lactam cell envelope antibiotics (see: http://en.wikipedia.org/wiki/Monobactam).
  • antibiotics of the lincomycin family include lincomycin, clindamycin, and clindamycin phosphate.
  • macrolide antibiotics include erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin, telithromycin, carbomycin A, josamycin, kitasamycin, midecamycin/midecamycin acetate, oleandomycin, solithromycin, spiramycin, troleandomycin, and tylosin/tylocine.
  • ketolide antibiotics include telithromycin, cethromycin, solithromycin, spiramycin, ansamycin, oleandomycin, carbomycin, and tylosin.
  • antibiotics of the tetracycline family include tetracycline itself, chlortetracycline, oxytetracycline, demeclocycline, rolitetracycline, methacycline and doxycycline.
  • sulfur-based antibiotics include the sulfonamides sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, sulfisoxazole, and sulfamethoxazole.
  • linkable antibiotics include the oxazolidinones such as zyvox (linezolid), peptide antibiotics such as the polymixins, quinolones, fluoroquinolones
  • Linkable antibiotics can also include various combinations
  • antibacterial agents antifungal agents, antimycotic agents and antiviral agents
  • penicillins such as ampicillin or amoxicillin, cephalosporins such as cephalothin and ceclor (cephachlor), aminoglycosides such as, kanamycin, macrolides such as erythromycin, nystatin, and amphotericin; and the antibiotics amikacin, bacillomycin, chloramphenicol, doxorubicin, doxycycline, ethambutol, erythromycin, gentamicin, isoniazid, kanamycin, carbacephalosporins such as lorabid (loracarbef), mupirocin, neomycin, pyrrolnitrin, rifampin, streptomycin, and vancomycin.
  • cephalosporins such as cephalothin and ceclor (cephachlor)
  • aminoglycosides such as, kanamycin, macrolides such as erythromycin, nystatin, and amphotericin
  • Preparation of the compounds described herein can be prepared according to the methods in the Examples below, or may be prepared according to known techniques in the art of organic synthesis.
  • Many linking groups for conjugating antibiotics to Formula (I) are commercially available, and/or can be prepared as described in the art. Information regarding general synthetic methods that may be used to prepare the compounds described herein, particularly with respect employing linking groups, may be found in Greg T. Hermanson, Bioconjugate Techniques, Academic Press, San Diego, CA (1996).
  • Useful linkers and conjugation techniques that can be used to link antibiotics to Formula (A) are further described by Roosenberg et al., Curr. Med. Chem. 2000, 7, 159; Wittmann et al., Bioorg. Med. Chem.
  • the methods of preparing compounds of the invention can produce isomers in certain instances. Although the methods of the invention do not always require separation of these isomers, such separation may be accomplished, if desired, by methods known in the art. For example, preparative high performance liquid chromatography methods may be used for isomer purification, for example, by using a column with a chiral packing.
  • Compounds of Formula (I) can be readily prepared by condensing an antibiotic having an available hydroxy or amine group, or a carboxy after reduction to an alcohol, with a compound of Formula (A):
  • Y is a leaving group such as a halogen (e.g., to couple with an amine or alcohol), for example, chloride.
  • a halogen e.g., to couple with an amine or alcohol
  • condensations can be carried out in the presence of a suitable solvent and a base (e.g., triethylamine or the like), often advantageously at or below room temperature.
  • a suitable solvent and a base e.g., triethylamine or the like
  • the hydroxyl group of the antibiotic can be directly coupled to form an ester or first esterified with a group such as an alkanoic acid having an terminal (optionally protected) amino group, for example, 2-aminoacetic acid or 3-aminopropionic acid, followed by a condensation reaction described above, to provide a compound of the invention.
  • the compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier.
  • the compounds may be added to a carrier in the form of a salt or solvate.
  • a pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.
  • the compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms.
  • the forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes.
  • the compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • compounds can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet.
  • Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations typically contain at least 0.1% of active compound.
  • compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form.
  • amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate.
  • a sweetening agent such as sucrose, fructose, lactose or aspartame
  • a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be
  • microorganisms maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers, or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and/or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization.
  • methods of preparation can include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution.
  • compounds may be applied in pure form, e.g., when they are liquids.
  • a dermatologically acceptable carrier which may be a solid, a liquid, a gel, or the like.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like.
  • Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • compositions for delivering active agents to the skin are known to the art; for example, see U.S. Patent Nos. 4,992,478 (Geria), 4,820,508
  • compositions described herein can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition
  • Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949 (Borch et al.).
  • the amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician.
  • the compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg/m 2 , conveniently 10 to 750 mg/m 2 , most conveniently, 50 to 500 mg/m of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the invention provides therapeutic methods of treating infections in a mammal, which involve administering to a mammal having an infection an effective amount of a compound or composition described herein.
  • a mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like.
  • the infection can be a bacterial infection, for example, one caused by a bacterium described herein.
  • the ability of a compound of the invention to treat a bacterial infection may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, quantification of cell kill, and the biological significance of the use of antibacterial screens are known. In addition, ability of a compound to treat a bacterial infection or kill or inhibit bacteria may be determined using the assays as described in the Examples below.
  • HPLC analyses were carried out using YMC Pro C18 reverse phase column (3.0x50 mm).
  • Mobile phases used were 10 mM ammonium acetate in HPLC grade water (A) and HPLC grade acetonitrile (B).
  • a gradient was formed from 5 -80 of B in 10 min, then 80 -95 of B in 2 min, and then 95 -5 of B in 3 min at a flow rate of 0.7 mL/min (total run time of 15 min).
  • Preparative HPLC purifications were performed on a Waters preparative binary pump system at a flow rate of 15 mL/min with a UV detector (254 nm) and a YMC-Pack Pro C18 column (150x20 mm, particle size 5 ⁇ ).
  • a solvent gradient was formed from 10 mM aqueous ammonium acetate and acetonitrile with a flow rate of 15 mL/min.
  • the following compounds were prepared according to published procedures: trinitrile 3 (Newkome et al., J. Org. Chem., 1988, 53, 5552-5554), methyl succinyl chloride (Cason, J. Org. Synth., 1945, 25, 19), and 2,3-diacetoxybenzoic acid (Bergeron et al., /. Org. Chem., 1980, 45, 1589-1592).
  • the structures of compounds 4-10 are illustrated in Figure 2.
  • Nitro tricarbamate 4 This compound was prepared by a modified two step literature procedure (Unciti-Broceta et al., /. Med. Chem., 2008, 51, 4076-4084). To a suspension of trinitrile 3 (3.30 g, 15.0 mmol) in 10 mL of anhydrous THF was added BH - THF complex (1.0 M in THF, 75 mL, 75.0 mmol). The solution was heated to reflux for 16 h. After cooling to room temperature (-22 °C), cone. HC1 was added to destroy the excess borane and the mixture was heated with steam bath for 30 min.
  • Methyl succinate 6 To a solution of compound 5 (1.12g, 2.23 mmol) and Et 3 N (0.62 mL, 4.46 mmol) in 10 mL of CH 2 CI 2 cooled to 0 °C was added methyl succinyl chloride (0.52 mL, 4.23 mmol). The mixture was stirred for 1 h at 0 °C and 1 h at room temperature. The solvent was removed under vacuum and the residue was partitioned between 50 mL of EtOAc and 50 mL of water. The aqueous layer was extracted with EtOAc (50 mLx3) and the combined organic layers were washed sequentially with sat. NaHC0 3 , brine, dried over Na 2 S0 4 and filtered. After removal of the solvent under vacuum, the residue was purified by chromatography on a silica gel column (50-100% EtOAc in hexanes) to give compound 6
  • 2,3-Diacyloxybenzoyl chloride 8 To a suspension of 2,3-diacetoxybenzoic acid (2.38 g, 10 mmol) in 30 mL of CH 2 C1 2 were added oxalyl chloride (1.72 mL, 20 mmol) and anhydrous DMF (0.1 mL). The solution was stirred at room temperature for 1 h and all solvent was removed under vacuum to give crude acyl chloride 8 as a yellow semi- solid which was used immediately in the next step.
  • Ampicillin conjugate 10 To a solution of acid 9 (22 mg, 0.023 mmol) and N-methyl morpholine (2.5 ⁇ , 0.023 mmol) in 1 mL of anhydrous THF cooled to 0 °C was added isobutyl chloroformate (3.0 ⁇ , 0.023 mmol) and the mixture was stirred for 1 hour at that temperature. A solution of ampicillin trihydrate (10.6 mg, 0.026 mmol) and Et N (10 ⁇ L) in 1 mL of THF/H 2 0 4: 1 was added and the mixture was stirred for 1 h at 0 °C and 1 h at room temperature.
  • conjugate 10 (16.4 mg, 55%) as a white solid: 1H NMR (600 MHz,
  • Iron-rich (+Fe) MHII broth was prepared by adding 0.8 mL of a 1 mg/mL sterile aq. solution of FeCl 3 to 49.2 mL of MHII broth.
  • Mueller-Hinton No. 2 agar (MHII agar; HiMedia Laboratories) was purchased from VWR.
  • Iron-deficient (-Fe) MHII agar was prepared by adding 0.5 mL of a 1 mg/mL sterile aq. solution of 2,2'-bipyridine to 34 mL of melted MHII agar with gentle mixing.
  • Iron-rich (+Fe) MHII agar was prepared by adding 0.5 mL of a 1 mg/mL sterile aq. solution of FeCl 3 to 34 mL of melted MHII agar with gentle mixing. See also Wencewicz, T. A. Dissertation, University of Notre Dame, Notre Dame, IN, 2011, for relevant techniques.
  • Antibacterial Susceptibility Testing by the Agar Diffusion Assay Antibacterial activity of the compounds was determined by a modified Kirby-Bauer agar diffusion assay. Overnight cultures of test organisms were grown in LB broth for 18-24 h and standard suspensions of 1.5xl0 6 CFU/mL were prepared in saline solution (0.9% NaCl) according to a 0.5 BaS0 4 McFarland Standard. This standardized suspension (0.1 mL) was added to 34 mL of sterile, melted agar (-Fe or +Fe) tempered to 47-50 °C.
  • the inoculated agar media was poured into a sterile plastic petri dish (145 mmx20 mm) and allowed to solidify near a flame with the lid ajar for about 30 min. Wells of 9.0 mm diameter were cut from the petri dish agar and filled with exactly 50 ⁇ ⁇ of the test sample solution. The petri dish was incubated at 37 °C for 18-24 h and the inhibition zone diameters were measured (mm) with an electronic caliper after 24 h.
  • MIC 90 Values by the Broth Microdilution Assay. Antibacterial activity of the compounds was determined by measuring their minimum inhibitory concentrations (MICgo's) using the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI, formerly the NCCLS) guidelines. Each well of a 96- well microtiter plate was filled with 50 ⁇ ⁇ of sterile broth media (-Fe or +Fe). Each test compound was dissolved in DMSO making a 20 mM solution, and then diluted with sterile broth media (-Fe or +Fe) to 400 or 800 ⁇ . Exactly 50 of the compound solution was added to the first well of the microtiter plate and 2-fold serial dilutions were made down each row of the plate.
  • CCSI Clinical and Laboratory Standards Institute
  • bacterial inoculum 5xl0 5 CFU/mL in broth media
  • the plate was incubated at 37 °C for 20 h and then each well was examined for bacterial growth.
  • the MIC 90 was recorded as the lowest compound concentration ( ⁇ ) required to inhibit 90% of bacterial growth as judged by turbidity of the culture media relative to a row of wells filled with a DMSO standard.
  • compositions illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Compound X'):
  • compositions may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest.

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EP13882608.6A 2013-04-18 2013-10-23 Antibakterielle siderophor-aminopenicillin-konjugate Withdrawn EP2986617A4 (de)

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US13/865,801 US9302012B2 (en) 2012-04-18 2013-04-18 Anti-bacterial siderophore-aminopenicillin conjugates
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US20210277023A1 (en) * 2018-05-09 2021-09-09 University Of Notre Dame Du Lac Antibiotic conjugates
EP3986882A4 (de) * 2019-06-24 2023-04-05 Diverse Biotech, Inc. Beta-lactam-cannabinoid-konjugatmoleküle
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RU2015144372A (ru) 2017-05-19
US9302012B2 (en) 2016-04-05
MX2015014621A (es) 2016-09-07
CA2909597A1 (en) 2014-10-23
BR112015026362A2 (pt) 2017-07-25
CN105636966A (zh) 2016-06-01
WO2014171971A1 (en) 2014-10-23
KR20160026856A (ko) 2016-03-09
EP2986617A4 (de) 2017-03-22
JP2016516813A (ja) 2016-06-09

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